tbuckley/cabot-search huggingface dataset:
Abstract 5966: Cathepsin S mediates interleukin 7 to sculpture the tumor immunity in head and neck cancer
Authors: Yung-Chieh Chang, Shan-Hung Chen, Kwang-Yu Chang, Jang-Yang Chang
Journal: Cancer Research (2023)

Abstract Cathepsin S (CTSS) is a lysosomal enzyme that belongs to cysteine proteases. It is associated with progression of different types of cancer, mediating the antigen presentation, extracellular matrix degradation, angiogenesis, and metastasis. In recent studies, CTSS was suggested as a therapeutic target for cancer treatment. We found that, with a CTSS inhibitor RJW-58 treatment over tumor-bearing mouse, the serum showed an enhanced anti-tumor cytokine releasing of interleukin 7 (IL-7). In the mRNA array results of 40 pair head and neck patients’ sample, we found the negative correlation between CTSS and IL-7 comparing to the normal head and neck tissue. Moreover, we also found that the level of CD8 T cell infiltration is negatively correlated with the expression of CTSS in 20 head and neck cancer patients’ slides. In cell model, targeting CTSS by siRNA or RJW-58 promoted IL-7 secretion in different head and neck cancer cell lines. We demonstrated that cathepsin S decreased the secretion level of IL-7 through downregulating IL-7 receptor, a receptor that mediating IL-7 secretion, protein expression level resulting in activating lysosomal degradation pathway. Promoting cell proliferation of activated CD8 T cells was proved when CD8 T cells were treated with the condition medium from CTSS-knockdown head and neck cancer cells. In conclusion, this is the first study demonstrated that CTSS acted as a negative regulator in mediating IL-7 resulting in inducing an immune cell-suppressed microenvironment in head and neck cancer cells. (This work is supported by the NSTC grand number: MOST 110-2314-B-400-035) Citation Format: Yung-Chieh Chang, Shan-Hung Chen, Kwang-Yu Chang, Jang-Yang Chang. Cathepsin S mediates interleukin 7 to sculpture the tumor immunity in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5966.
Abstract 6085: Molecular profile by next generation sequencing in papillary thyroid carcinoma, Colombian Cohort at Fundacion Santa fe de Bogota University Hospital
Authors: Paula Rodriguez, Sebastián González, Sergio Cruz, Yesith Juez, David Becerra, Margarita Baldión, Sandra Perdomo, Angela Beltran, Jose Hakim, Deyanira Gonzales
Journal: Cancer Research (2023)

Abstract Objective/aim: To describe the main molecular alterations in a Colombian Cohort of patients diagnosed with Papillary Thyroid Carcinoma (PTC) at Fundacion Santa Fe de Bogota University Hospital between 1993 and 2011 Methods: A total of 231 surgically intervened patients at our institution and diagnosed with PTC with available paraffin blocks were analysed. DNA and RNA extraction was performed from FFPE samples using Quick-DNA &amp; RNA FFPE MiniPrep Kit (Zymo Research). Next Generation Sequencing analysis was performed using SOPHiA Solid Tumor Solutions Kit (SOPHiA GENETICS, Saint Sulpice, Suiza), which detects 42 DNA genes and 137 fusion genes with the platform MiSeq System (Illlumina, San Diego, California). Data underwent QA and QC and variants were analysed through Sophia commercial pipeline for somatic aberrations. Results: Among 231 patients, 82% were women, average age 45 +/- 13 y-o, 97% from Colombia, with institutional pathologic diagnosis of PTC. The most frequent histological subtypes were Classic PTG (33%), Follicular Infiltrative (29%) and Tall cell (23%). Identification of clinically relevant molecular alterations was done (see table 1). The most frequent SNV mutations were BRAF-V600E (72%), TP53 (9%) and IDH1-R132H (8%). The most frequent insertions or deletions (INDELS) were found in KIT (75%). We identified 8 fusion genes (most frequent were RET-CCD6 and ETV6-NTRK3). Interestingly, we detected 3 MSI positive cases. Conclusions: PTC molecular profile by NGS can allow us to improve molecular understanding of the disease and identify possible prognostic factors and treatment targets. Table 1. Molecular alterations detected by next-generation sequencing in Papillary carcinoma Molecular alterations Gene n % INDEL (n=20) KIT 15 75,0 NRAS 1 5,0 PTPN11 1 5,0 TP53 3 15 SNV (n=226) BRAF 163 72,1 FGFR1 1 0,4 HRAS 2 0,9 IDH1 19 8,4 KIT 2 0,9 KRAS 2 0,9 NRAS 9 4,0 PDGFRA 1 0,4 PIK3CA 3 1,3 SMAD4 4 1,8 TP53 20 8,8 Fusion genes (n=6) CCDC6-RET 2 25,0 ETV6-NTRK3 2 25,0 GOLGB1-TACC3 1 12,5 MYH14-BICC1 2 25,0 GOPC-RET 1 12,5 MSI (n=231) MSI-L 3 1,3 Negative 228 98,7 Citation Format: Paula Rodriguez, Sebastián González, Sergio Cruz, Yesith Juez, David Becerra, Margarita Baldión, Sandra Perdomo, Angela Beltran, Jose Hakim, Deyanira Gonzales. Molecular profile by next generation sequencing in papillary thyroid carcinoma, Colombian Cohort at Fundacion Santa fe de Bogota University Hospital [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6085.
Abstract 6720: Using proteasome inhibition to hyperactivate the integrated stress response in aggressive pediatric brain tumors
Authors: Orlandi Valencia Novak, Tyler Findlay, Jeffrey Rubens, Charles Eberhart, Eric H. Raabe
Journal: Cancer Research (2023)

Abstract H3K27-altered diffuse midline glioma (DMG) and atypical teratoid/rhabdoid tumor (AT/RT) are aggressive pediatric brain tumors with dismal outcomes. DMG and AT/RT have increased baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that enables cells to tolerate various forms of stress. This activation is manifested by elevated levels of ATF4 and NRF2 in DMG and AT/RT, respectively. Transient or low-level expression of these transcription factors protect cells from stress, while sustained, high-level activation leads to cell death. Ixazomib is an orally bioavailable proteasome inhibitor that causes endoplasmic reticulum stress, which is a major upstream activator of the ISR. We hypothesized that the high baseline level of ATF4 in DMG and NRF2 in AT/RT would make these tumors susceptible to ISR activators such as ixazomib. After determining the IC50 of ixazomib, DMG and AT/RT cell lines (JHH-DIPG1, JHH-DIPG16A, and CHLA06) were treated with increasing concentrations of the drug. Cleaved caspase 3 immunofluorescence showed a significant increase of apoptosis in all cell lines (JHH-DIPG16A and CHLA06 p&amp;lt;0.0001, JHH-DIPG1 p=0.0008 by ANOVA). Additionally, western blots for cleaved PARP and phospho-Rb expression detected induction of apoptosis and suppression of cell proliferation in JHH-DIPG1 treated with ixazomib. We are currently testing ixazomib in combination with idarubicin, a brain-penetrant anthracycline, and gemcitabine, a brain-penetrant nucleoside analog. Synergy testing in CHLA06 showed an overall zero-interaction-potency (ZIP) synergy score of 23.464 with inhibitory concentrations of ixazomib and idarubicin in the low nanomolar range (scores of 10 or above indicate synergy). Similarly, ixazomib and gemcitabine synergized to suppress CHLA06 growth and induce apoptosis (67% Annexin V+ cells in combination compared to 14 and 24% Annexin V+ with single agent treatment). In the future, we will determine if ixazomib selectively kills DMG and AT/RT while sparing normal cells in iPSC brain organoids. We will also test ixazomib singly and in combination with traditional chemotherapy in orthotopic xenografts of AT/RT. These results suggest that ixazomib, especially in combination with idarubicin, gemcitabine or other ISR activators, has the potential to serve as an effective therapy for aggressive pediatric brain tumors. Citation Format: Orlandi Valencia Novak, Tyler Findlay, Jeffrey Rubens, Charles Eberhart, Eric H. Raabe. Using proteasome inhibition to hyperactivate the integrated stress response in aggressive pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6720.
Abstract 1492: Interaction between Argonaute-2 and Negative Elongation Factor-E in hepatocellular carcinoma
Authors: Brittany Natalie Ruiz, Alvaro Lucci, Anna Barry, Kai Zhang, Hien Dang
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) continues to be one of the leading cause of cancer-related deaths globally, whose incidence is on the rise in the United States. We and others have shown that high levels of AGO2 is associated with a worse prognosis in HCC patients. Specifically, we showed AGO2 promotes HCC progression by modulating MYC mRNA stability in an RNAi-independent manner. In addition to its canonical role as an RNA binding protein, AGO2 has been demonstrated to regulate gene expression by affecting RNA polymerase II (Pol II) pausing through the Negative Elongation Factor (NELF) complex in Drosophila. It remains elusive how AGO2 modulates the chromatin to affect transcription. Here, we hypothesize AGO2/NELF interactions modulate chromatin accessibility to promote HCC. Immunoprecipitation assays were employed to detect protein-protein interactions between AGO2 and the NELF complex in HCC cells. To determine the effects of AGO2 RNAi-silencing on their interaction, DICER-knockout (via CRISPR) HCC cell lines were also probed for protein-protein interactions. We found AGO2 and NELFE, a member of the NELF complex, interact in both wild-type and DICER-knockout HCC cell lines. These data suggest AGO2 may play an important role in modulating transcription through NELF. Currently, we are investigating the potential interplay between AGO2 and NELFE in modulating chromatin accessibility to promote hepatocarcinogenesis. Understanding the effects of the AGO2/NELF interaction may help elucidate transcriptional regulation in HCC and lead to better therapies for HCC patients. Citation Format: Brittany Natalie Ruiz, Alvaro Lucci, Anna Barry, Kai Zhang, Hien Dang. Interaction between Argonaute-2 and Negative Elongation Factor-E in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1492.
Abstract 4160: Characterization of cytotoxic resilient T cells in patients with advanced cancers in response to salvage radiation therapy or chemotherapy
Authors: Joanina K. Gicobi, Yiyi Yan, Hu Zeng, Sean Park, Haidong Dong
Journal: Cancer Research (2023)

Abstract Although cancer burden in patients with advanced diseases results in T cell exhaustion and failed prior therapies, some of them achieved durable clinical responses to salvage therapy (chemotherapy or radiation therapy) implying a presence of tumor-reactive resilient T cells in them. However, the phenotype and functional features of resilient T cells have not been clearly defined. We found that CX3CR1+ CD8+ T cells with low mitochondrial membrane potential demonstrated features of resilient T cells: (a) their cytotoxic T cell function (degranulation/CD107a expression) recovered quickly after tumor burden has been reduced by radiation therapy or chemotherapy; (b) they maintain a low profile of glycolysis but produce optimal levels of ATP; (c) they express lower levels of PD-1 and TOX; (4) they share a feature of stem-like T cells (TCF1+PD-1+) that can be responsive to immunotherapy; (5) they avoid accumulation of a harmful level of cytosolic reactive oxygen species (ROS) that may cause T cell exhaustion; (6) they upregulate malic enzyme 1 (ME1) to balance glycolysis and ROS, and to expand cytotoxic effector T cells. These unique features of resilient T cells may not only be used as T cell biomarker to design rational combination therapy to control advanced cancers but can also be used to convey a resilient functional state to T cells in patients who lack them. Citation Format: Joanina K. Gicobi, Yiyi Yan, Hu Zeng, Sean Park, Haidong Dong. Characterization of cytotoxic resilient T cells in patients with advanced cancers in response to salvage radiation therapy or chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4160.
Abstract 5948: MAGE-A3 expression with MMR-MSH6 screening suggests MAGE-A3 as a potential target for microsatellite-stable colorectal cancer
Authors: Jina Yom, Rachel Gonzalez, Eden Zewdu, Aubrey Su, Patrick Yin, Bailey Gilmore, Dehe Kong, Andy Han, Zhaoying Guo, Tianli Qu, Zoe Zhao, Eric Christenson, Yan Ma, Hailey Guo, Xiaomin Hu, Qi Ren, Zhaohui Wu, Xuan Liu, Wei Fu
Journal: Cancer Research (2023)

Abstract Colorectal Cancer (CRC) is the second leading cause of death worldwide. Recent developments in cancer immunotherapy have obtained encouraging clinical responses, including PD-1/PD-L1 blockade therapy, although response rates vary depending on tumor type. For example, despite the lack of response by microsatellite-stable CRC, a subset of CRC with deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H) responds especially well to the PD-1/PD-L1 blockade therapy. For other types of CRC which do not respond to PD-L1 therapy, new targets are being investigated. One family of targets is the cancer testis antigen MAGE-A whose expression is restricted to germline cells in normal tissue but is overexpressed in many cancer cells. In this study, immunohistochemical analysis of MAGE-A3 expression in colon cancer along with IHC screening of mismatch protein MSH6 was performed. Many of the cases in this study observed a co-expression in the tissue. In the tumors, MAGE-A3 was observed to have weak cytoplasmic expression while MSH6 had strong nuclear expression in the epithelial cells. The immune cells adjacent to the epithelial cells were also positive for MAGE-A3. This result suggests that MAGE-A3 may be a promising target for microsatellite-stable colorectal cancer immunotherapy. Citation Format: Jina Yom, Rachel Gonzalez, Eden Zewdu, Aubrey Su, Patrick Yin, Bailey Gilmore, Dehe Kong, Andy Han, Zhaoying Guo, Tianli Qu, Zoe Zhao, Eric Christenson, Yan Ma, Hailey Guo, Xiaomin Hu, Qi Ren, Zhaohui Wu, Xuan Liu, Wei Fu. MAGE-A3 expression with MMR-MSH6 screening suggests MAGE-A3 as a potential target for microsatellite-stable colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5948.
Abstract 3141: Epiregulon infers single-cell transcription factor activity to dissect mechanisms of lineage plasticity and drug response
Authors: Tomasz Wlodarczyk, Jenille Tan, Kerstin Seidel, Diana Wu, Shang-Yang Chen, Aleksander Chlebowski, Timothy Keyes, Yu Guo, Aaron Lun, Christopher Siebel, Shiqi Xie, Xiaosai Yao
Journal: Cancer Research (2023)

Abstract Single-cell multiomic technologies enable holistic reconstruction of cell states and hold the potential to identify drivers of tumor evolution and drug resistance. However, the data sparsity of single-cell assays can preclude accurate estimation of transcription factor activity. In addition, gene expression alone cannot capture transcription factor activity, especially in the context of drug treatment which alters transcription factor function without suppressing gene expression. To circumvent these challenges, we have developed epiregulon, a R package that constructs gene regulatory networks and infers transcription factor (TF) activity in single cells by integrating single cell gene expression, chromatin accessibility and bulk TF occupancy data. Epiregulon applies tests of independence to identify likely transcription factor - regulatory element - target gene relationships occurring at joint probabilities exceeding the expected probabilities of independent events. With epiregulon, we are able to detect lineage factor activity at enhanced sensitivity and predict perturbations more accurately than gene expression could. We further applied this tool to understand transcription factor activity to enzalutamide treatment and identify potential drivers of enzalutamide resistance. Finally, we generated a ground truth dataset using reprogram-seq, a technology that captures multi-omic profiles of single cells upon expression of defined transcription factors. Epiregulon correctly predicts NKX2-1 targets and demonstrates that NKX2-1 expression reprograms the epigenome towards a neuroendocrine state in LNCaP cells. Epiregulon is a useful tool that constructs gene regulatory networks to model the underlying gene regulation hierarchies that drive gene expression and cell states. Citation Format: Tomasz Wlodarczyk, Jenille Tan, Kerstin Seidel, Diana Wu, Shang-Yang Chen, Aleksander Chlebowski, Timothy Keyes, Yu Guo, Aaron Lun, Christopher Siebel, Shiqi Xie, Xiaosai Yao. Epiregulon infers single-cell transcription factor activity to dissect mechanisms of lineage plasticity and drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3141.
Abstract 4738: Dysregulated miR-371b-5p/CSDE1/RAC1 axis is involved in pathogenesis of triple-negative breast cancer
Authors: Yesol Kim, Je Yeong Ko, Soo-Been Lee, Jaehee Jun, Yejin Ahn, Jinui Min, Chaewon Oh, Jong Hoon Park
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer; however, pathogenesis of TNBC has not yet been fully understood. Here, we identified dysregulated microRNAs (miRNAs) by analyzing miRNA microarray of TNBC patients. MiR-371b-5p expression was reduced, and ectopic expression of miR-371b-5p significantly inhibited TNBC progression in vitro and in vivo. In addition, we found that expression of cold shock domain-containing protein E1 (CSDE1), a direct target gene of miR-371b-5p, was upregulated in TNBC cells, and inhibition of CSDE1 alleviated TNBC cell growth by decreasing RAC1 known as pro-metastatic gene. Mechanistically, CSDE1, phosphorylated C-terminal domain (p-CTD) of RNA polymerase II (RNAPII), and CDK7 form a complex, and downregulation of CSDE1 results in weak interaction between RNAPII p-CTD and CDK7, which leads to a decrease in RNAPII p-CTD expression to reduce RAC1 transcript levels in CSDE1-deficient TNBC cells. Our data revealed the oncogenic function of miR-371b/CSDE1 involved in Rac1 transcription regulation, thus providing a basis for the pathological mechanism of TNBC along with potential biomarkers for TNBC. Citation Format: Yesol Kim, Je Yeong Ko, Soo-Been Lee, Jaehee Jun, Yejin Ahn, Jinui Min, Chaewon Oh, Jong Hoon Park. Dysregulated miR-371b-5p/CSDE1/RAC1 axis is involved in pathogenesis of triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4738.
Abstract 4794: Deciphering tumor recurrence post-therapy: Interactions between the tumor microenvironment and therapy-induced senescent glioblastoma
Authors: Valerie DeLuca, Priya Digumarti, Michael E. Berens
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) remains one of the most lethal forms of cancer due, in part, to the capacity of tumor cells to persist during therapy and then recover. Understanding how these residual tumor cells survive is therefore imperative to developing more effective treatment strategies. We have demonstrated that GBM cells, including those from patient-derived xenografts, undergo a state of therapy-induced senescence (TIS) rather than cell death following temozolomide (TMZ) and radiation (IR). Both TMZ and IR treatment at physiologically relevant doses result in elevated senescence-associated-β-galactosidase, altered morphology, p21 induction, and increased expression of the senescence-associated-heterochromatic-foci marker H3K9Me3. Further, despite TIS-induction in a majority of the residual cells post-treatment, GBM viable cell number increases after a prolonged stasis, indicating that populations are capable of reentering a proliferative state. However, our current understanding of how the tumor microenvironment influences this growth arrest and subsequent proliferative recovery is underdeveloped. We aim to bridge that gap by investigating the paracrine communications between astrocytes and GBM cells undergoing IR-induced senescence in order to identify how these interactions foster disease progression. Current studies are focused on evaluating the effect of astrocytes on the induction and durability of TIS in GBM cells. Proteomic studies will be pursued to characterize the secretome of astrocyte-GBM co-cultures and identify factors that drive GBM senescent response to IR. Finally, based on preliminary data demonstrating that normal astrocytes are also damaged by IR, we will undertake mechanistic studies to understand how cell-intrinsic events within the astrocyte population drive extrinsic-influence on GBM cells. We anticipate that these identified signaling events may serve as potential therapeutic targets. Citation Format: Valerie DeLuca, Priya Digumarti, Michael E. Berens. Deciphering tumor recurrence post-therapy: Interactions between the tumor microenvironment and therapy-induced senescent glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4794.